3-(α-Substituted-benzyl)-2,3-dihydrothiazolo [3,2-a][1,3]diazacyclan-3-ol derivatives

ABSTRACT

This disclosure describes certain novel 3-(α-substituted-benzyl)-2,3-dihydrothiazolo[3,2-a][1,3]diazacyclan-3-ols which are useful as diuretic agents.

BRIEF SUMMARY OF THE INVENTION

This invention relates to new organic compounds and, more particularly,is concerned with novel3-(α-substituted-benzyl)-2,3-dihydrothiazolo[3,2-a][1,3]diazacyclan-3-olswhich may be represented by the following structural formula: ##STR1##wherein Q is a divalent moiety selected from the group consisting ofthose of the formulae: ##STR2## wherein n is the integer 1, 2 or 3; R₁is hydrogen, fluoro, chloro, bromo, alkyl having from 1 to 3 carbonatoms or alkoxy having from 1 to 3 carbon atoms; R₂ is hydrogen or themoiety ##STR3## wherein R₁ is as hereinbefore defined; R₃ is hydrogen,alkyl having from 1 to 3 carbon atoms or a moiety selected from thegroup consisting of those of the formulae: ##STR4## wherein R₁ and R₂are as hereinbefore defined. The invention also includes novelcompositions of matter containing the above-defined compounds useful asdiuretics and the method of enhancing the excretion of sodium ions inmammals therewith.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds of the present invention are generally obtainable aswhite to pale yellow crystalline materials having characteristic meltingpoints and absorption spectra and which may be purified byrecrystallization from common organic solvents such as methanol,ethanol, N,N-dimethylformamide, acetone, chloroform, ethyl acetate, andthe like. They are appreciably soluble in non-polar organic solventssuch as toluene, carbon tetrachloride, and the like but are relativelyinsoluble in water. The organic bases of this invention form nontoxicacid-addition salts with a variety of pharmacologically acceptableorganic and inorganic salt-forming reagents. Thus, acid-addition salts,formed by admixture of the organic free base with one or two equivalentsof an acid, suitably in a neutral solvent, are formed with such acids assulfuric, phosphoric, hydrochloric, hydriodic, sulfamic, citric, lactic,fumaric, succinic, tartaric, acetic, benzoic, gluconic, ascorbic, andthe like. The acid-addition salts are relatively insoluble in non-polarorganic solvents such as diethyl ether, benzene, toluene, and the likebut are appreciably soluble in water. For purposes of this invention,the free bases are equivalent to their non-toxic acid-addition salts.

The novel compounds of the present invention may be readily prepared asset forth in the following reaction scheme: ##STR5## wherein R₁, R₂, R₃and Q are as hereinabove defined. In accordance with this reactionscheme, a 1-aryl-2-alkanone (1) is dissolved in acetic acid and treatedwith about one equivalent of bromine at 60°-70° C., giving thebromo-1-aryl-2-alkanone (2). This alkanone (2) is isolated and reactedwith cyclic thiourea (3) to give the product (4). If chloride is used inplace of bromine, the hydrochloride salt is obtained.

In general terms, the process of step one may be carried out in aceticacid or an equivalent at 50°-80° C. for 30 minutes to 4 hours. Suitablesolvents for the second step include acetone, methylethylketone,chloroform, benzene, toluene and the like and the reaction may rangefrom 25°-60° C. for one to 72 hours. Procedures for the preparation ofthe 1-aryl-2-alkanones (1) are well known and may be found in suchreferences as: M. J. Hatch and D. J. Cram, J.A.C.S., 75, 38 (1953); E.J. Cragoe, Jr., A. M. Pietruszkiewicz and C. M. Robb, J. Org. Chem., 23,971 (1958); E. M. Schultz, U.S. Pat. No. 2,703,329. It is also possibleto prepare the halo-1-aryl-2-alkanone derivatives (2) by other methods,for example, the Arndt-Eistert synthesis of an acid chloride withdiazomethane and hydrobromic or hydrochloric acid [G. W. Wheland,(Advanced Organic Chemistry), John Wiley and Sons, Inc., 2nd Edition, P.462 (1948)] .

Alternatively, the compounds of Formula (4) may be prepared by treatinga compound of the structure ##STR6## with compounds of the generalstructure ##STR7## where X is a halogen other than fluorine, and R₁, R₂and R₃ are as indicated above. The process is carried out by the actionof a compound of the structure (6a) or (6b) upon a compound of structure(5) in an inert solvent such as diethyl ether, tetrahydrofuran, and thelike, at temperatures ranging from 0° to 40° C., preferably at roomtemperature, for a period of 3 to 18 hours, and under an inert gas(argon or nitrogen) atmosphere. After hydrolysis of the intermediateadducts, the compounds of structure (4) are readily isolated as the freebases, which can then be converted to the desired acid addition salts.

The compounds of formula (4) can also be depicted in the equivalenttautomeric structure, ##STR8## but infra-red spectral analysis of thecrystalline products indicates that structure (4) is the predominant, ifnot the sole, configuration present. For purposes of convenience,structure (4) will be employed, but it is to be understood that allcompounds of structures (4) and (7), as well as their optical isomersare in the purview of this application.

These new compounds possess diuretic activity in warm-blooded animals asestablished when tested by the method of P. S. Chan and D. Poorvin,Clinical and Experimental Hypertension, 1 (6), 817-830 (1979),"Sequential Method for Combined Screening Antihypertensive and DiureticAgents in the Same Spontaneously Hypertensive Rat." Basically this testuses male, 8 week old, spontaneously hypertensive rats of the Okamotostrain weighing about 300 g. One rat is dosed by gavage with the testcompound at 100 mg./kg. of body weight with 0.9% sodium chloride loadingat 25 ml./kg. of body weight at zero hour. The test compound issuspended in 2% preboiled starch at 50 mg./kg. The rat is placed in ametabolism cage and the 0-5 hour urine is collected. The urinary sodium,potassium and chloride content are determined by the TechniconAutoanalyzer; method N-20 for sodium and potassium and method N-5b forchloride. At the end of the fifth hour, the rat is placed in a regularanimal cage and provided with water ad libitum. A second identical doseof the test compound is given by gavage, without sodium chlorideloading, at the 24th hour. Four hours later, the rat is restrained in asupine position with elastic tapes. The femoral area is locallyanesthetized by subcutaneous infiltration of 2% lidocaine. The iliacartery is isolated and punctured with a 26 gauge thin wall needle whichis connected to a Statham P23Db pressure transducer-Beckman Dynographrecorder system for monitoring blood pressure. The blood pressure isrecorded for 15 minutes or until it is stabilized. Based on the dataobtained and using the three-stage "sequential probability ration test",statistical method, the criteria for determining if a test compound isconsidered active are as follows:

Test I:

If the mean arterial blood pressure (MABP) ≦116 and/or the urinarysodium is ≧1.21 mEq the compound is active. If the MABP is between117-146 and/or the urinary sodium is between 1.21-0.93, a second rat istested.

Test II:

If the average MABP of the two rats is <122 and/or the average urinarysodium of the two rats is >1.16 mEq, the compound is considered active.If the MABP is between 123-137 and/or the average urinary sodium isbetween 1.16-1.01, a third rat is tested.

Test III:

If the average MABP of the three rats is ≦128 and/or the average urinarysodium is ≧1.10, the compound is active.

The results of these tests on representative compounds of the presentinvention appear in Table I.

                                      TABLE I                                     __________________________________________________________________________                              Urinary Values in                                                             mEq/5 Hours                                         Compound                  Volume(ml.)                                                                          Na.sup.+                                                                         K.sup.+                                   __________________________________________________________________________    3-Diphenylmethyl-2,3,5,6,7,8-hexahydrothiazolo[3,2-a]-                                                  21.8   2.56                                                                             0.69                                      [1,3]diazepin-3-ol hydrobromide                                               3-(p-Chloro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydrothia-                                            10.8   1.33                                                                             0.71                                      zolo[3,2-a][1,3]diazepin-3-ol hydrobromide                                    3-(p-Fluoro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydrothia-                                            16.0   2.05                                                                             0.76                                      zolo[3,2-a][1,3]diazepin-3-ol hydrobromide                                    3-(p-Bromo-α-phenylbenzyl)-2,3,5,6,7,8-hexahydrothia-                                             13.8   1.68                                                                             0.62                                      zolo[3,2-a][1,3]diazepin-3-ol hydrobromide                                    3-[o-Chloro-α-(p-fluorophenyl)benzyl]-2,3,5,6,7,8-                                                11.5   1.53                                                                             0.68                                      hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol                                    hydrobromide                                                                  3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,6,7,8-                                                12.3   1.64                                                                             0.52                                      hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol                                    hydrobromide                                                                  3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,6,7,8-                                                13.5   1.88                                                                             0.77                                      hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol                                    hydrobromide                                                                  3-(p-Chloro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydro-2-                                              17.5   2.15                                                                             0.79                                      methylthiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                          3-(p-Fluoro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydro-2-                                              22.0   2.82                                                                             0.63                                      methylthiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                          3-Diphenylmethyl-2,3,6,7-tetrahydro-5H-thiazolo-                                                        16.5   1.76                                                                             0.70                                      [3,2-a]pyrimidin-3-ol hydrobromide                                            3-(p-Bromo-α-phenylbenzyl)-2,3,6,7-tetrahydro-5H-                                                 11.3   1.41                                                                             0.58                                      thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                                    3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetra-                                              14.8   1.92                                                                             0.60                                      hydro-5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                           3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetra-                                              18.0   2.23                                                                             0.62                                      hydro-5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                           3-[bis(p-Fluorophenyl)methyl]-2,3,6,7-tetrahydro-5H-                                                    19.0   2.47                                                                             0.59                                      thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                                    3-(p-Chloro-α-phenylbenzyl)-2,3,6,7-tetrahydro-2-                                                 15.0   1.63                                                                             0.91                                      methyl-5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                          3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-2-                                                 16.5   2.04                                                                             0.40                                      methyl-5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                          3-Diphenylmethyl-2,3,6,7-tetrahydro-6,6-dimethyl-5H-                                                    14.5   2.04                                                                             0.73                                      thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                                    3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-6,6-                                               12.3   1.63                                                                             0.72                                      dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol hydro-                              bromide                                                                       3-(p-Bromo-α-phenylbenzyl)-2,3,6,7-tetrahydro-6,6-                                                14.3   1.55                                                                             0.72                                      dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol hydro-                              bromide                                                                       3-[p-Chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetra-                                              15.0   1.61                                                                             0.99                                      hydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                           hydrobromide                                                                  3-[o-Chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetra-                                              19.3   2.18                                                                             0.80                                      hydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                           hydrobromide                                                                  3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetra-                                              15.5   2.02                                                                             0.74                                      hydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                           hydrobromide                                                                  3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetra-                                              15.0   1.77                                                                             0.86                                      hydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                           hydrobromide                                                                  3-[bis(p-Fluorophenyl)methyl]-2,3,6,7-tetrahydro-6,6-                                                   13.5   1.97                                                                             0.99                                      dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol hydro-                              bromide                                                                       3-(p-Chloro-α-phenylbenzyl)-2,3,6,7-tetrahydro-2,6,6-                                             11.5   1.40                                                                             0.76                                      trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                    hydrobromide                                                                  3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-2,6,6-                                             16.5   2.04                                                                             0.80                                      trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                    hydrobromide                                                                  3-[o-Chloro-α-(p-fluorophenyl)benzyl]-2,3,5,8-tetra-                                              11.8   1.37                                                                             0.58                                      hydrothiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                           3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,8-tetra-                                              18.0   2.08                                                                             0.68                                      hydrothiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                           3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,8-tetra-                                              15.5   1.70                                                                             0.60                                      hydrothiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                           3-Diphenylmethyl-2,3,6,7,8,9-hexahydro-5H-thiazolo-                                                     19.3   2.77                                                                             1.90                                      [3,2-a][1,3]diazocin-3-ol hydrobromide                                        3-Benzyl-2-phenyl-2,3,6,7-tetrahydro-5H-thiazolo-                                                       10.8   1.32                                                                             0.48                                      [3,2-a]pyrimidin-3-ol hydrobromide                                            3-Benzyl-6,6-dimethyl-2-phenyl-2,3,6,7-tetrahydro-                                                      15.8   2.14                                                                             0.57                                      5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                                 3-(p-Fluorobenzyl)-2-p-fluorophenyl-2,3,5,6,7,8-                                                        14.0   1.87                                                                             0.62                                      hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol hy-                                drobromide                                                                    3-(p-Fluorobenzyl)-2-p-fluorophenyl-2,3,6,7,8,9-                                                        20.0   2.10                                                                             0.75                                      hexahydro-5H-thiazolo[3,2-a][1,3]diazocin-3-ol                                hydrobromide                                                                  __________________________________________________________________________

The active compounds of the present invention are effective as diureticsin warm-blooded animals when administered in amounts ranging from about5 mg. to about 200 mg. per kilogram of body weight per day. A preferreddosage regimen for optimum results would be from about 5 mg. to about 50mg. per kilogram of body weight per day, and such dosage units areemployed that a total of from about 350 mg. to about 3.5 g. of theactive compound for a subject of about 70 kg. of body weight areadministered in a 24 hour period. This dosage regimen may be adjusted toprovide the optimum therapeutic response. For example, several divideddoses may be administered daily or the dose may be proportionallyreduced as indicated by the exigencies of the therapeutic situation. Adecided practical advantage is that these active compounds may beadministered in any convenient manner such as by the oral, intravenous,intramuscular, or subcutaneous routes.

The active compounds may be orally administered, for example, with aninert diluent or with an assimilable edible carrier, or they may beenclosed in hard or soft shell gelatin capsules, or they may becompressed into tablets, or they may be incorporated directly with thefood of the diet. For oral therapeutic administration, these activecompounds may be incorporated with excipients and used in the form ofingestible tablets, buccal tablets, troches, capsules, elixirs,suspensions, syrups, wafers and the like. Such compositions andpreparations should contain at least 0.1% of active compound. Thepercentage of the compositions and preparations may, of course, bevaried and may conveniently be between about 2% to about 60% of theweight of the unit. The amount of active compound in suchtherapeutically useful compositions is such that a suitable dosage willbe obtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 5 and and 200 mg. of active compound.

The tablets, troches, pills, capsules and the like may also contain thefollowing: A binder such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, lactose or saccharin may be added or a flavoring agent such aspeppermint, oil of wintergreen or cherry flavoring. When the dosage unitform is a capsule, it may contain, in addition to materials of the abovetype, a liquid carrier. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with shellac,sugar or sucrose as a sweetening agent, methyl and propylparabens aspreservatives, a dye and flavoring such as cherry or orange flavor. Ofcourse, any material used in preparing any dosage unit form should bepharmaceutically pure and substantially non-toxic in the amounts used.In addition, these active compounds may be incorporated intosustained-release preparations and formulations.

These active compounds may also be administered parenterally orintraperitoneally. Solutions or suspensions of these active compounds asa free base or pharmacologically acceptable salt can be prepared inwater suitably mixed with a surfactant such as hydroxypropylcellulose.Dispersions can also be prepared in glycerol, liquid polyethyleneglycols, and mixtures thereof in oils. Under ordinary conditions ofstorage and use, these preparations contain a preservative to preventthe growth of microorganisms.

The pharmaceutical forms suitable for injectable use include sterileaqueous solutions or dispersions and sterile powders for theextemporaneous preparation of sterile injectable solutions ordispersions. In all cases, the form must be sterile and must be fluid tothe extent that easy syringability exists. It must be stable under theconditions of manufacture and storage and must be preserved against thecontaminating action of microorganisms such as bacteria and fungi. Thecarrier can be a solvent or dispersion medium containing, for example,water, ethanol, polyol (e.g. glycerol, propylene glycol and liquidpolyethylene glycol), suitable mixtures thereof, and vegetable oils.

The intermediate arylketones [formula (1)] are prepared essentially asdescribed by Cragoe, et al., vide supra, as illustrated in Example 1.

EXAMPLE 1 1-(m-Fluorophenyl)-1-(p-fluorophenyl)-2-propanone

A solution of 16.5 g. or m-fluorophenyl-2-propanone [Z. Eckstein and J.Plenkiewicz, Rocznik. Chem., 37, 907 (1963)] in 70 ml. of fluorobenzeneis cooled and stirred as 5.5 ml. of bromine are added dropwise. Argongas is bubbled through the mixture for one hour. The solution is thenadded dropwise to a mixture of 29.6 g. of aluminum chloride and 70 ml.of fluorobenzene, stirred at 80°-90° C. Stirring is continued at thistemperature for one hour then the mixture is poured into ice and 45 ml.of concentrated hydrochloric acid. Toluene is added, the organic layeris separated, washed with dilute sodium hydroxide and then water anddistilled, giving the desired product as a liquid, b.p. 106°-112°C./0.15 mm.

When the appropriate 1-aryl-2-alkanone is reacted with a benzenederivative (as reagent and solvent) by the procedure described inExample 1, the intermediates Examples 2-21 (listed in tabular form) arederived.

    __________________________________________________________________________     ##STR9##                                                                      ##STR10##                                                                    1-Aryl-2- Benzene                                                             alkanone  Derivative                                                          Ex.                                                                              R.sub.1                                                                           R.sub.3                                                                          R.sub.2                                                                             Intermediate        B.P. °C./mm.                       __________________________________________________________________________    2  H   H  p-Cl  1-(p-Chlorophenyl)-1-phenyl-2-propanone                                                           150-156/0.4                               3  H   H  p-F   1-(p-Fluorophenyl)-1-phenyl-2-propanone                                                           142-146/<1                                4  H   H  p-Br  1-(p-Bromophenyl)-1-phenyl-2-propanone                                                            134-138/0.15                              5  H   H  p-CH.sub.3                                                                          1-Phenyl-1-p-tolyl-2-propanone                                                                    140-144/<1                                6  m-Cl                                                                              H  p-CH.sub.3                                                                          1-(m-Chlorophenyl)-1-p-tolyl-2-propanone                                                          130-136/0.2                               7  o-F H  p-CH.sub.3                                                                          1-(o-Fluorophenyl)-1-p-tolyl-2-propanone                                                          130-136/0.2                               8  m-F H  p-CH.sub.3                                                                          1-(m-Fluorophenyl)-1-p-tolyl-2-propanone                                                          111-120/0.2                               9  p-CH.sub.3                                                                        H  p-F   1-(p-Fluorophenyl)-1-p-tolyl-2-propanone                                                          116-122/0.15                              10 m-CH.sub.3                                                                        H  p-CH.sub.3                                                                          1-m-Tolyl-1-p-tolyl-2-propanone                                                                   126-132/0.2                               11 p-Cl                                                                              H  p-Cl  1,1-bis(p-Chlorophenyl)-2-propanone                                                               170-178/<1                                12 p-Cl                                                                              H  p-F   1-(p-Chlorophenyl)-1-(p-fluorophenyl)-2-                                                          130-136/0.2                                               propanone                                                     13 o-Cl                                                                              H  p-F   1-(o-Chlorophenyl)-1-(p-fluorophenyl)-2-                                                          114-120/0.15                                              propanone                                                     14 o-F H  p-F   1-(o-Fluorophenyl)-1-(p-fluorophenyl)-2-                                                          100-106/0.15                                              propanone                                                     15 m-Cl                                                                              H  p-F   1-(m-Chlorophenyl)-1-(p-fluorophenyl)-2-                                                          126-135/0.15                                              propanone                                                     16 p-F H  p-F   1,1-bis(p-Fluorophenyl)-2-propanone                                                               120-126/0.2                               17 m-CH.sub.3                                                                        H  p-F   1-(p-Fluorophenyl)-1-m-tolyl-2-propanone                                                          116-122/0.15                              18 H   CH.sub.3                                                                         p-Cl  1-(p-Chlorophenyl)-1-phenyl-2-butanone                                                            155-160/<1                                19 H   CH.sub.3                                                                         p-F   1-(p-Fluorophenyl)-1-phenyl-2-butanone                                                            142-146/>1                                20 p-F CH.sub.3                                                                         p-F   1,1-bis(p-Fluorophenyl)-2-butanone                                                                128-132/0.4                               21 p-Cl                                                                              CH.sub.3                                                                         p-Cl  1,1-bis(p-Chlorophenyl)-2-butanone                                                                162-168/0.2                               __________________________________________________________________________

EXAMPLE 223-Diphenylmethyl-2,3,5,6,7,8-hexahydrothiazolo[3,2-a][1,3]diazepin-3-olhydrobromide

A solution of 4.20 g. of 1,1-diphenyl-2-propanone in 25 ml. of aceticacid is heated at 60°-70° C. and 1.0 ml. of bromine in 8 ml. of aceticacid is added dropwise. The reaction mixture is held at 60°-70° C. forone hour and then poured into ice. Toluene is added. The toluene layeris separated, washed with water, dried over magnesium sulfate andconcentrated to obtain 1-bromo-3,3-diphenyl-2-propanone.

The 1-bromo-3,3-diphenyl-2-propanone is dissolved in 30 ml. of acetoneand added to a boiling mixture of 1.82 g. ofhexahydro-2H-1,3-diazepine-2-thione in 100 ml. of acetone. This mixtureis allowed to stand at room temperature for 24 hours, then the productis collected by filtration, washed with acetone and dried in vacuo at50° C., giving the product as a solid, m.p. 194°-195° C. (dec.).

When the procedure of Example 22 is carried out using, instead of1,1-diphenyl-2-propanone, the intermediate diarylketones of Examples1-21, the final products of Examples 23-39 (listed in tabular form) arederived.

    __________________________________________________________________________     ##STR11##                                                                     ##STR12##                                                                       Inter-                                                                        mediate                                                                    Ex.                                                                              Ex. No.                                                                            Product                  M.P. °C.                              __________________________________________________________________________    23 2    3-(p-Chloro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydro-                                               202-204                                              thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        24 3    3-(p-Fluoro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydro-                                               183-185                                              thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        25 4    3-(p-Bromo-α-phenylbenzyl)-2,3,5,6,7,8-hexahydro-                                                169-171                                              thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        26 5    2,3,5,6,7,8-Hexahydro-3-(p-methyl-α-phenylbenzyl)-                                               198-200                                              thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        27 7    3-(o-Fluoro-α-p-tolylbenzyl)-2,3,5,6,7,8-hexahy-                                                 176-178                                              drothiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                     28 9    3-(p-Fluoro-α-p-tolylbenzyl)-2,3,5,6,7,8-hexahy-                                                 184-186                                              drothiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                     29 10   2,3,5,6,7,8-Hexahydro-3-(m-methyl-α-p-tolyl-                                                     191-193                                              benzyl)thiazolo[3,2-a][1,3]diazepin-3-ol hydro-                               bromide                                                               30 12   3-[p-Chloro-α-(p-fluorophenyl)benzyl]-2,3,5,6,7,8-                                               197-199                                              hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol hydro-                             bromide                                                               31 13   3-[o-Chloro-α-(p-fluorophenyl)benzyl]-2,3,5,6,7,8-                                               175-177                                              hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol hydro-                             bromide                                                               32 14   3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,6,7,8-                                               204-206                                              hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol hydro-                             bromide                                                               33 1    3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,6,7,8-                                               189-191                                              hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol hydro-                             bromide                                                               34 16   3-[bis(p-Fluorophenyl)methyl]-2,3,5,6,7,8,hexahy-                                                      187-189                                              drothiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                     35 17   3-(p-Fluoro-α-m-tolylbenzyl)-2,3,5,6,7,8-hexahy-                                                 180-182                                              drothiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                     36 18   3-(p-Chloro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydro-                                               187-189                                              2-methylthiazolo[3,2-a]diazepin-3-ol hydrobromide                     37 19   3-(p-Fluoro-α-phenylbenzyl)-2,3,5,6,7,8-hexahydro-                                               198-200                                              2-methylthiazolo[3,2][1,3]diazepin-3-ol hydrobro-                             mide                                                                  38 20   3-[bis(p-Fluorophenyl)methyl]-2,3,5,6,7,8-hexahydro-                                                   192-194                                              2-methylthiazolo[3,2-a] [1,3]diazepin-3-ol hydrobro-                          mide                                                                  39 21   3-[bis(p-Chlorophenyl)methyl]-2,3,5,6,7,8-hexahydro-                                                   197-199                                              2-methylthiazolo[3,2-a][1,3]diazepin-3-ol hydrobro-                           mide                                                                  __________________________________________________________________________

EXAMPLE 403-Diphenylmethyl-2,3,5,6,7,8-hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol

A solution of 4.2 g. of3-diphenylmethyl-2,3,5,-6,7,8-hexahydrothiazolo[3,2-a][1,3]diazepin-3-olhydrobromide in 50 ml. of 65% aqueous methanol is treated with 12 ml. of1 N sodium hydroxide. The resulting solid is collected by filtration,washed with water and dried in vacuo at 40° C., giving the desiredproduct, m.p. 123°-125° C.

EXAMPLE 413-Diphenylmethyl-2,3,5,6,7,8-hexahydrothiazolo[3,2-a][1,3]diazepin-3-olhydrochloride

A solution of 3.0 g. of3-diphenylmethyl-2,3,5,-6,7,8-hexahydrothiazolo[3,2-a][1,3-diazepin-3-olin 30 ml. of acetone is treated with 4 ml. of 3 N ethanolic hydrochloricacid. The resulting solid is collected by filtration, giving the desiredproduct, m.p. 205° C. (dec.).

EXAMPLE 423-Diphenylmethyl-2,3,6,7-tetrahydro-5H-thiazolo-[3,2-a]pyrimidin-3-olhydrobromide

A 2.1 g. portion of 1,1-diphenyl-2-propanone is converted to1-bromo-3,3-diphenyl-2-propanone by the procedure of Example 22. The1-bromo-3,3-diphenyl-2-propanone is dissolved in 15 ml. of acetone andadded to a boiling mixture of 0.80 g. of tetrahydro-2-pyrimidinethionein 70 ml. of acetone. This mixture is allowed to stand for 48 hours andthe resulting solid is collected by filtration, giving the desiredproduct, m.p. 196°-198° C.

When the procedure of Example 40 is carried out using, instead of1.1-diphenyl-2-propanone, the intermediate diarylketones of Examples1-21, the final products of Examples 43-60 (listed in tabular form) arederived.

    __________________________________________________________________________     ##STR13##                                                                     ##STR14##                                                                       Inter-                                                                        mediate                                                                    Ex.                                                                              Ex. No.                                                                            Product                  M.P. °C.                              __________________________________________________________________________    43 2    3-(p-Chloro-α-phenylbenzyl)-2,3,6,7-tetrahydro-5H-                                               177-179                                              thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                            44 3    3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-5H-                                               174-176                                              thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                            45 4    3-(p-Bromo-α-phenylbenzyl)-2,3,6,7-tetrahydro-5H-                                                163-166                                              thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                            46 5    2,3,6,7-Tetrahydro-3-(p-methyl-α-phenylbenzyl)-5H-                                               163-165                                              thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                            47 6    3-(m-Chloro-α-p-tolylbenzyl)-2,3,6,7-tetrahydro-                                                 184-186                                              5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                         48 7    3-(o-Fluoro-α-p-tolybenzyl)-2,3,6,7-tetrahydro-                                                  188-190                                              5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                         49 8    3-(m-Fluoro-α-p-tolylbenzyl)-2,3,6,7-tetrahydro-                                                 138-140                                              5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                         50 9    3-(p-Fluoro-α-p-tolybenzyl)-2,3,6,7-tetrahydro-                                                  135-137                                              5H-thiazolo[3,2-a]pyrimid-3-ol hydrobromide                           51 10   2,3,6,7-Tetrahydro-3-(m-methyl-α-p-tolylbenzyl)-                                                 173-175                                              5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                         52 11   3-[bis(p-Chlorophenyl)methyl-2,3,6,7-tetrahydro-                                                       131-133                                              5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                         53 12   3-[p-Chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-                                                   144-146                                              tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-ol                           54 13   3-[o-Chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-                                                   184-186                                              tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-ol                                   hydrobromide                                                          55 14   3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-                                                   190-192                                              tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-ol                                   hydrobromide                                                          56 1    3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-                                                   154-156                                              tetrahydro-5H-thiazolo]3,2-a]pyrimidin-3-ol                                   hydrobromide                                                          57 16   3-[bis(p-Fluorophenyl)methyl]-2,3,6,7-tetrahydro-                                                      172-174                                              5H-thiazolo[3,2-a]pyrimidin-3-ol hydrobromide                         58 18   3-(p-Chloro-α-phenylbenzyl)-2,3,6,7,-tertahydro-2-                                               176-178                                              methyl-5H-thiazolo[3,2-a]pyrimidin-3-ol hydro-                                bromide                                                               59 19   3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-                                                  213-215                                              2-methyl-5H-thiazolo[3,2-a]pyrimidin-3-ol hydro-                              bromide                                                               60 20   3-[bis(p-Fluorophenyl)methyl]-2-methyl-2,3,6,7,-                                                       183-5                                                tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-ol hy-                               drobromide.                                                           __________________________________________________________________________

EXAMPLE 613-Diphenylmethyl-2,3,6,7-tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide

A 2.1 g. portion of 1,1-diphenyl-2-propanone is converted to1-bromo-3,3-diphenyl-2-propanone as described in Example 22. This1-bromo-3,3-diphenyl-2-propanone is dissolved in 15 ml. of acetone andadded to a boiling mixture of 1.0 g. oftetrahydro-5,5-dimethyl-2(1H)-pyrimidinethione in 50 ml. of acetone. Themixture is allowed to stand at room temperature for 24 hours and theresulting solid is collected by filtration, giving the desired product,m.p. 259°-261° C.

When the procedure of Example 61 is carried out using, instead of1,1-diphenyl-2-propanone, the intermediate diarylketones of Examples1-21, the final products of Examples 62-78 (listed in tabular form) arederived.

    __________________________________________________________________________     ##STR15##                                                                     ##STR16##                                                                       Inter-                                                                        mediate                                                                    Ex.                                                                              Ex. No.                                                                            Product                 M.P. °C.                               __________________________________________________________________________    62 2    3-(p-Chloro-α-phenylbenzyl)-2,3,6,7-trahydro-                                                   ca 180                                                6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          63 3    3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-                                                 ca 200                                                6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          64 4    3-(p-Bromo-α-phenylbenzyl)-2,3,6,7-tetrahydro-                                                  180                                                   6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          65 5    2,3,6,7-Tetrahydro-3-(p-methyl-α-phenylbenzyl)-                                                 169-171                                               6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          66 6    3-(m-Chloro-α-p-tolybenzyl)-2,3,6,7-tetrahydro-                                                 ca 200                                                6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          67 7    3-(o-Fluoro-α-p-tolybenzyl)-2,3,6,7-tetrahydro                                                  170-172                                               6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          68 9    3-(p-Fluoro-α-p-tolylbenzyl)-2,3,6,7-tetrahydro-                                                <200                                                  6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          69 12   3-[p-Chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-                                                  192-194                                               tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]-                                   pyrimidin-3-ol hydrobromide                                           70 13   3[o-Chloro-α-(p-fluorophenyl)benyl)benzyl-2,3,6,7-                                              205                                                   tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]-                                   pyrimidin-3-ol hydrobromide                                           71 14   3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-                                                  ca 220                                                tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]-                                   pyrimidin-3-ol hydrobromide                                           72 1    3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-                                                  203                                                   tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]-                                   pyrimidin-3-ol-hydrobromide                                           73 16   3-[bis-(p-Flourophenyl)methyl]-2,3,6,7-tetra-                                                         198-200                                               hydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-                               3-ol hydrobromide                                                     74 17   3-(p-Fluoro-α-m-tolylbenzyl)-2,3,6,7-tetrahydro-                                                ca 200                                                6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                 hydrobromide                                                          75 18   3-(p-Chloro-α-phenylbenzyl)-2,3,6,7-tetrahydro-                                                 166-168                                               trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                                    hydrobromide                                                          76 19   3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7,-tetrahydro-                                                175-177                                               2,6,6-trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                              hydrobromide                                                          77 20   3-[bis(p-Fluorophenyl)methyl]-2,3,6,7,-tetrahydro-                                                    192-3                                                 2,6,6,-trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-ol                             hydrobromide                                                          78 21   3-[bis(p-Chlorophenyl)methyl]  -2,3,6,7-tetrahydro-                                                   198-200                                               2,6,6,-trimethyl-5H-thiazolo[3,2,-a]pyrimidin-3-ol                            hydrobromide                                                          __________________________________________________________________________

EXAMPLE 793-[bis(p-Fluorophenyl)methyl]-6,6-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-oland its monohydrochloride

22.8 grams of3-[bis(p-Fluorophenyl)methyl]-6,6-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a][1,3]-pyrimidin-3-olhydrobromide is dissolved in 100 ml. of methanol, employing slightwarming. The solution is then treated with 10 ml. of 5 N sodiumhydroxide. A white precipitate soon develops. The mixture is cooled at5° C., the precipitate collected, washed with water and dried; yield,17.5 grams of the free base; M.P. 145°-7°. The free base is dissolved inethanol and treated with 15 ml. of 4.4 N ethanolic hydrogen chloride.Removal of the solvent in vacuo (bath temperature 50°) leaves a whiteresidue which after triturating with 200 ml. acetone yields 14.5 gramsof the title compound, melting at 293°-295° C.

EXAMPLE 803-(p-Fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-2,6,6-trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-oland its monohydrochloride

63.0 grams of3-(p-Fluoro-α-phenylbenzyl)-2,3,6,7,-tetrahydro-2,6,6-trimethyl-5H-thiazolo[3,2-a][1,3]pyrimidin-3-olhydrobromide is dissolved in 400 ml. of methanol, and the solution thentreated with 30 ml. of 5 N sodium hydroxide, followed by 400 ml. ofwater. After cooling at 5° C., the precipitate is washed with water, anddried; yield of free base, 37.7 g; M.P. 138°-140° C. The free base isdissolved in 400 ml. of warm ethanol and the solution then treated with40 ml. of 3.7 N ethanolic hydrogen chloride. Addition of 150 ml. ofacetone gives a precipitate of the title compound, which after washingwith acetone and drying, weighs 34.7 g. and melts at 193°-195° C., withdecomposition.

EXAMPLE 813-[bis(p-Fluorophenyl)methyl]-2,3,6,7-tetrahydro-2,6,6-trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-oland its monohydrochloride

40 grams of3-[bis(p-fluorophenyl)methyl]-2,3,6,7-tetrahydro-2,6,6-trimethyl-5H-thiazolo[3,2-a][1,3]pyrimidin-3-olhydrobromide is dissolved in 150 ml. of methanol, and the solution thentreated with 20 ml. of 5 N sodium hydroxide. The mixture is cooled to 5°C., the precipitate is collected, washed with water, and dried, yielding20.0 grams of the free base; M.P. 146°-148° C. The free base isdissolved in 200 ml. of ethanol, and then treated with 20 ml. of 3.7 Nethanolic hydrogen chloride. The solution is concentrated in vacuo at50° C., until crystallization occurs. The mixture is diluted with anequal volume of acetone. The precipitate is collected, washed withacetone and dried, yielding 15.0 grams of the title compound, melting at184°-186° C., with decomposition.

EXAMPLE 823-Diphenylmethyl-2,3,5,8-tetrahydrothiazolo[3,2-a][1,3]-diazepin-3-olhydrobromide

A 4.2 g. portion of 1,1-diphenyl-2-propanone is converted to1-bromo-3,3-diphenyl-2-propanone by the procedure of Example 22.

This 1-bromo-3,3-diphenyl-2-propanone is dissolved in 50 ml. of acetoneand added to a warm solution of 1.28 g. of1,3,4,7-tetrahydro-2H-1,3-diazepin-2-thione in 100 ml. of acetone. Thereaction mixture is warmed, with stirring, for 3 hours and then stirredfor 72 hours. The mixture is cooled and the resulting solid is collectedby filtration, giving the desired product.

When the procedure of Example 82 is carried out using, instead of1,1-diphenyl-2-propanone, the intermediate diarylketones of Examples1-21, the final products of Examples 83-91 (listed in tabular form) arederived.

    __________________________________________________________________________     ##STR17##                                                                     ##STR18##                                                                       Inter-                                                                        mediate                                                                    Ex.                                                                              Ex. No.                                                                            Product                 M.P. °C.                               __________________________________________________________________________    83 2    3-(p-Chloro-α-phenylbenzyl)-2,3,5,8-tetrahydro-                                                 183-185                                               thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        84 5    2,3,5,8-Tetrahydro-3-(p-methyl-α-phenylbenzyl)-                                                 177-179                                               thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        85 6    3-(m-Chloro-α-p-tolylbenzyl)-2,3,5,8-tetrahydro-                                                168-171                                               thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        86 8    3-(m-Fluoro-α-p-tolylbenzyl)-2,3,5,8-tetrahydro-                                                155-165                                               thiazolo[3,2-a][1,3] diazepin-3-ol hydrobromide                       87 17   3-(p-Fluoro-α-m-tolylbenzyl)-2,3,5,8-tetrahydro-                                                181-183                                               thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        88 13   3-[o-Chloro-α-(p-fluorophenyl)benzyl]-2,3,5,8-                                                  204-206                                               tetrahydrothiazolo[3,2-a][1,3]diazepin-3-ol                                   hydrobromide                                                          89 14   3-[o-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,8-                                                  210-212                                               tetrahydrothiazolo[3,2-a][1,3]diazepin-3-ol                                   hydrobromide                                                          90 1    3-[m-Fluoro-α-(p-fluorophenyl)benzyl]-2,3,5,8-                                                  176-178                                               tetrahydrothiazolo[3,2-a][1,3]diazepin-3-ol                                   hydrobromide                                                          91 16   3-[bis(p-Fluorophenyl)methyl]-2,3,5,8-tetrahydro-                                                     174-176                                               thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide                        __________________________________________________________________________

EXAMPLE 923-Diphenylmethyl-2,3,6,7,8,9-hexahydro-5H-thiazolo[3,2-a][1,3]diazocin-3-olhydrobromide

1-Bromo-3,3-diphenyl-2-propanone is reacted withhexahydro-1,3-diazocin-2(1H)-thione by the procedure of Example 22,giving the desired product, m.p. 211°-213° C. (dec.).

EXAMPLE 93 1-Bromo-1,3-diphenyl-2-propanone

The synthesis of the requisite 1,3-diaryl-2-propanones is readilyaccomplished by a variety of synthetic procedures (see "SyntheticOrganic Chemistry", R. B. Wagner and H. D. Zook, John Wiley and Sons[publisher], New York, N.Y., 1953). They are also conveniently obtainedas a high boiling residue in the preparation of 1-aryl-2-propanones##STR19##

A solution of 8.4 grams of 1,3-diphenyl-2-propanone in 80 ml. ofmethylene chloride is stirred as a solution of 1.5 ml. of bromine in 30ml. of methylene chloride is added dropwise. The loss of brominecoloration in the reaction solution is very rapid. The methylenechloride is then removed in vacuo (bath temperature 40° C.), and theresidual 1-bromo-1,3-diphenyl-2-propanone is utilized directly insubsequent chemical reactions.

Additional 1,3-diaryl-2-propanones (Examples 94-99), prepared by theprocedure cited in Example 93, are listed in tabular form. They areconverted to their bromo derivatives by the same procedure as describedin Example 93.

    ______________________________________                                         ##STR20##                                                                     ##STR21##                                                                    1,3-Diaryl-2-propanone                                                        Example    R.sub.1   M.P. or B.P.                                             ______________________________________                                        94         m-F       b.p. 128°-132° C. (0.2mm.)                 95         p-F       m.p. 62°-4° C.                             96         p-Cl      m.p. 97°-99° C.                            97         p-Br      M.P. 118°-120° C.                          98         m-CH.sub.3                                                                              b.p. 130°-134° C. (0.15mm.)                99         p-CH.sub.3                                                                              m.p. 53°-55° C.                            ______________________________________                                    

EXAMPLE 1003-Benzyl-2,3,6,7-tetrahydro-2-phenyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide

A solution of 2.9 grams of 1-bromo-1,3-diphenyl-2-propanone (Example 93)in 30 ml. of acetone is added to a solution of 1.16 grams oftetrahydro-2-pyrimidinethione in 100 ml. of acetone. A white precipitateforms in a few minutes. After standing at room temperature for fourhours, the precipitate is collected, washed with acetone, and dried.Recrystallization from 20 ml. of ethanol yields 2.3 grams of the purecompound, melting at 192°-194° C. with decomposition.

When the procedures of Examples 93 and 100 are applied, utilizing the1,3-diaryl-2-propanones of Examples 93-99, and the listed cyclicthioureas, the final products of Examples 101-117 (listed in tabularform) are obtained.

    __________________________________________________________________________     ##STR22##                                                                     ##STR23##                                                                       Inter-                                                                        mediate                                                                    Ex.                                                                              Ex. No.                                                                            Q            Product                 M.P. °C.                  __________________________________________________________________________    101                                                                              95   (CH.sub.2).sub.3                                                                           3-(p-Fluorobenzyl-2-(p-fluorophenyl-2,3,6,7-                                                          193-195                                               tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-ol                                   hydrobromide                                             102                                                                              98                                                                                  ##STR24##   6,6-Dimethyl-3-(m-methylbenzyl-2,3,6,7-tetra-                                 hydro-2-m-tolyl-5H-thiazolo[3,2-a]pyrimidin-3- ol                             hydrobromide            185-187                          103                                                                              97                                                                                  ##STR25##   3-p-bromobenzyl-2-p-bromophenyl-6,6-dimethyl-                                 2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin- 3-ol                          hydrobromide            186-187                          104                                                                              99                                                                                  ##STR26##   6,6-dimethyl-3-(p-methylbenzyl)-2,3,6,7-tetra-                                hydro-2-p-tolyl-5H-thiazolo[3,2-a]pyrimidin-3- ol                             hydrobromide            163-165                          105                                                                              93                                                                                  ##STR27##   3-benzyl-6,6-dimethyl-2-phenyl-2,3,6,7-tetra-                                 hydro-5H-thiazolo[3,2-a]pyrimidin-3-ol hydro-                                 bromide                 153-155                          106                                                                              95                                                                                  ##STR28##   6,6-dimethyl-3-(p-fluorobenzyl)-2-p-fluorophenyl-                             2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin- 3-ol                          hydrobromide            181-183                          107                                                                              93   (CH.sub.2).sub.4                                                                           3-benzyl-2,3,5,6,7,8-hexahydro-2-phenylthiazolo-                                                      165-167                                               [3,2-a][1,3]diazepin-3-ol hydrobromide                   108                                                                              95   (CH.sub.2).sub.4                                                                           3-p-fluorobenzyl-2-p-fluorophenyl-2,3,5,6,7,8-                                                        166-168                                               hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol hy-                                drobromide                                               109                                                                              99   (CH.sub.2).sub.4                                                                           2,3,5,6,7,8-Hexahydro-3-m-methylbenzyl-2-m-tolyl-                                                     184-186                                               thiazolo[3,2-a][1,3]diazepin-3-ol hydrobromide           110                                                                              94   (CH.sub.2).sub.4                                                                           3-m-fluorobenzyl-2-m-fluorophenyl-2,3,5,6,7,8-                                                        178-180                                               hexahydrothiazolo[3,2-a][1,3]diazepin-3-ol hy-                                drobromide                                               111                                                                              95   CH.sub.2 CHCHCH.sub.2                                                                      3-p-fluorobenzyl-2-p-fluorophenyl-2,3,5,8-tetra-                              hydrothiazolo[3,2-a][1,3]diazepin-3-ol hydrobro-                              mide                                                     112                                                                              93   (CH.sub.2).sub.5                                                                           3-benzyl-2,3,6,7,8,9-hexahydro-2-phenyl-5H-thia-                                                      193-195                                               zolo[3,2-a][1,3]diazocin-3-ol hydrobromide               113                                                                              95   (CH.sub.2).sub.5                                                                           3-p-fluorobenzyl-2-p-fluorophenyl-2,3,6,7,8,9-                                                        205-207                                               hexahydro-5H-thiazolo[3,2-a][1,3]diazocin-3-ol                                hydrobromide                                             114                                                                              94   (CH.sub.2).sub.5                                                                           3-m-fluorobenzyl-2-m-fluorophenyl-2,3,6,7,8,9-                                                        189-191                                               hexahydro-5H-thiazolo[3,2-a][1,3]diazocin-3-ol                                hydrobromide                                             115                                                                              96   (CH.sub.2).sub.5                                                                           3-p-chlorobenzyl-2-p-chlorophenyl-2,3,6,7,8,9-                                                        206-208                                               hexahydro-5H-thiazolo[3,2-a][1,3]diazocin-3-ol                                hydrobromide                                             116                                                                              99   (CH.sub.2).sub.5                                                                           2,3,6,7,8,9-hexahydro-3-p-methylbenzyl-2-p-                                                           168-170                                               tolyl-5H-thiazolo[3,2-a][1,3]diazocin-3-ol                                    hydrobromide                                             117                                                                              97   (CH.sub.2).sub.5                                                                           3-p-bromobenzyl-2-p-bromophenyl-2,3,6,7,8,9-                                                          212-214                                               hexahydro-5H-thiazolo[3,2-a][1,3]diazocin-3-                                  ol hydrobromide                                          __________________________________________________________________________

EXAMPLE 1183-Benzyl-6,6-dimethyl-2-phenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-ol

Sixty five and seven-tenths grams of2-benzyl-6,6-dimethyl-3-phenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a][1,3]pyrimidin-3-olhydrobromide (Example 94A) is dissolved in 400 ml. of methanol and thesolution then treated, successively, with 35 ml. of 5 normal sodiumhydroxide solution and 400 ml. of water. Concentration of the solutionin vacuo to remove the methanol yields a suspension of the titlecompound in water. The precipitate is collected, washed with water anddried. The yield is 56.0 grams and the product melts at 150°-152° C.

EXAMPLE 1193-Benzyl-6,6-dimethyl-2-phenyl-2,3,6,7-tetrahydro-5H-thiazolo]3,2-a]pyrimidin-3-olhydrochloride

Fifty three grams of3-benzyl-6,6-dimethyl-2-phenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a][1,3]pyrimidin-3-oland 400 ml. of acetone are combined and stirred vigorously as 160 ml. of1.1 N hydrogen chloride solution in ethanol is added during a fiveminute period. The mixture is then stirred another two hours, theprecipitate collected, washed with acetone and dried. There is obtained44.6 grams of the title compound, melting at 160°-162° C. withdecomposition.

We claim:
 1. A compound selected from those of the formula: ##STR29##wherein R₁ is hydrogen, fluoro, chloro, bromo, alkyl having from 1 to 3carbon atoms or alkoxy having from 1 to 3 carbon atoms; R₂ is hydrogenor ##STR30## wherein R₁ is as hereinbefore defined; R₃ is hydrogen,alkyl having from 1 to 3 carbon atoms, or a moiety selected from thegroup consisting of those of the formulae: ##STR31## wherein R₁ and R₂are as hereinbefore defined, and Q is a divalent moiety selected fromthe group consisting of those of the formulae: ##STR32## as well as thepharmaceutically acceptable salts thereof.
 2. The compound according toclaim 1,3-diphenylmethyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 3. The compound according to claim 1,3-[m-fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 4. The compound according to claim 1,3-[bis(p-fluorophenyl)methyl]-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 5. The compound according to claim 1,3-(p-fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-2-methyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 6. The compound according to claim 1,3-diphenylmethyl-2,3,6,7-tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]-pyrimidin-3-olhydrobromide.
 7. The compound according to claim 1,3-(p-fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 8. The compound according to claim 1,3-[o-chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 9. The compound according to claim 1,3-[o-fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7,-tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 10. The compound according to claim 1,3-[bis(p-fluorophenyl)methyl]-2,3,6,7-tetrahydro-6,6-dimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 11. The compound according to claim 1,3-(p-fluoro-α-phenylbenzyl)-2,3,6,7-tetrahydro-2,6,6-trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrochloride.
 12. The compound according to claim 1,3-[bis(p-fluorophenyl)methyl]-2,3,6,7-tetrahydro-2,6,6-trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrochloride.
 13. The compound according to claim 1,3-benzyl-2-phenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 14. The compound according to claim 1,3-[p-chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 15. The compound according to claim 1,3-[p-chloro-α-phenyl)benzyl]-2-methyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 16. The compound according to claim 1,3-(p-chloro-α-phenyl)benzyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 17. A compound according to claim 1,3-[o-fluoro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 18. A compound according to claim 1,3-[p-bromo-α-phenyl)benzyl]-2,3,6,7,tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 19. A compound according to claim 1,3-(p-fluoro-α-phenyl)benzyl-2-methyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 20. A compound according to claim 1,3-[o-chloro-α-(p-fluorophenyl)benzyl]-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 21. A compound according to claim 1,3-[bis(p-fluorophenyl)methyl]-2-methyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 22. A compound according to claim 1,3-(p-chloro-α-phenyl)benzyl-6,6-dimethyl-2,3,6,7-tetrahydrothiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 23. A compound according to claim 1,3-[m-fluoro-α-(p-fluorophenyl)benzyl]-6,6-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 24. A compound according to claim 1,3-(p-chloro-α-phenyl)benzyl-2,3,6,7-tetrahydro-2,6,6-trimethyl-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 25. A compound according to claim 1,3-(p-bromo-α-phenyl)benzyl-6,6-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 26. A compound according to claim 1,3-[p-fluoro-α-(m-tolyl)benzyl]-6,6-dimethyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.
 27. A compound according to claim 1,3-benzyl-6,6-dimethyl-2-phenyl-2,3,6,7-tetrahydro-5H-thiazolo[3,2-a]pyrimidin-3-olhydrobromide.